The present invention relates to a spectral imaging method for determining physicochemical properties and characteristics of a crystalline particulate substance, and more particularly, to a method for generating intra-particle crystallographic parameter maps and histograms of a chemically pure crystalline particulate substance, by spectral imaging of individual particles of the chemically pure crystalline particulate substance and analyzing the spectral images using pattern recognition classification analysis.
In the field of commercial handling, processing, and manufacturing, of crystalline particulate substances, including analysis and control thereof, especially as applied in the biopharmaceutical industry, there is on-going interest, resources, and activities, being devoted to techniques for measuring, determining, and analyzing, physicochemical data and information relating to crystallographic properties, characteristics, and parameters, of crystalline particulate substances, in general, and of chemically pure crystalline particulate substances, in particular.
In the highly regulated biopharmaceutical industry, an important stage during research and development of a new therapeutic product such as a natural or synthetic drug, high performance chemical, or, micro-organism, featuring at least one chemically pure crystalline particulate substance either in the raw material(s) and/or in the eventual finished pharmaceutical product formulated as a tablet capsule, caplet, or loose powder, involves extensive and well documented laboratory analytical testing of the physicochemical properties and characteristics of each chemically pure crystalline particulate substance. Analogous, but less stringent activities are also performed in the regulated food and beverage industries, regarding research and development of a new food or beverage product such as a natural or synthetic food or beverage ingredient, additive, high performance chemical, or, micro-organism, functioning as a flavor, a preservative, or, a consistency enhancer, featuring at least one chemically pure crystalline particulate substance either in the raw material(s) and/or in the eventual finished food or beverage product formulated as a stand alone compact or loose powder, or, as a compact or loose powder as part of another food or beverage product.
In a crystalline solid, herein, referred to as a crystalline particulate substance, to be distinguished from noncrystalline substances such as liquids and amorphous solids or amorphous particulate substances, structurally, the constituent particles, compounds, atoms, molecules, or ions, are arranged in an orderly, repetitive pattern or crystal structure in three dimensions. Herein, the term xe2x80x98chemically pure crystalline particulate substancexe2x80x99 refers to a crystalline particulate substance featuring a plurality of crystalline particles each composed of at least one chemically pure individual chemical compound, where the chemically pure crystalline particulate substance is typically heterogeneous with respect to morphological or geometrical distribution and/or with respect to frequency distribution of physicochemical properties and characteristics, such as concentration, density, particle size, particle geometry; particle shape, particle porosity, and crystallographic parameters of crystal type and crystal class, of the at least one chemically pure individual compound throughout a given sized sample of the chemically pure crystalline particulate substance.
In the biopharmaceutical industry, information about the physicochemical properties and characteristics of each chemically pure crystalline particulate substance are needed in a later stage for performing pharmacodynamical studies, involving metabolic and efficacy studies of the therapeutic product when ingested by an animal or human during pre-clinical and clinical studies. Metabolic information about the therapeutic product is needed for designing and evaluating efficacy studies, where the effectiveness of the therapeutic product for performing the indicated therapeutic function in a subject is measured. Ultimately, information and data from the efficacy studies are used for establishing the final formulation and recommended dosage levels of the new therapeutic product, for large scale dispensing to the consumer market. Correspondingly, data and information about the final formulation are used for establishing standardized quality control parameters and criteria for full-scale manufacturing of the new therapeutic product. Again, analogous, but less stringent activities are also performed in the regulated food and beverage industries, regarding each chemically pure crystalline particulate substance eventually ending up in a new food or beverage product, for large scale distribution to the consumer market.
Full-scale manufacturing of such a new or current, therapeutic, or, food or beverage, product, involves extensive and well documented standardized quality control testing of each chemically pure crystalline particulate raw material and/or each chemically pure crystalline particulate finished product, according to established quality control and quality assurance parameters and criteria. Similar to the research and development stages of such a product, this involves laboratory analytical testing and classification of the physicochemical properties and characteristics of each chemically pure crystalline particulate substance comprising the therapeutic, or, food or beverage, product.
Laboratory analytical testing of such a chemically pure crystalline particulate substance, during research and development stages or during routine finished product quality control testing, typically includes measuring and determining physicochemical properties and characteristics, such as concentration, density, particle size, particle geometry, particle shape, particle porosity, and/or crystallographic parameters, of a sample of the chemically pure crystalline particulate substance, in a statistically meaningful manner. Typically, such laboratory testing also includes measuring and determining dissolution properties of each applicable or selected chemically pure crystalline particulate substance. Dissolution testing provides data and information about the kinetics and thermodynamics of dissolution of a given chemically pure crystalline particulate substance in a variety of solvents. As indicated above, in the biopharmaceutical industry, such detailed information about the physicochemical properties and characteristics of each chemically pure crystalline particulate substance is valuable and used for either understanding, classifying, or quality control testing pharmacodynamical behavior of the therapeutic product.
It is well known in the field of physical chemistry of crystalline particulate matter, that dissolution properties and behavior of a crystalline particle, and therefore, of a sample of a crystalline particulate substance featuring a plurality of crystalline particles, in a liquid medium, either in-vitro or in-vivo, are, in varying degrees, related to and functions of morphological distribution and/or frequency distribution of physicochemical properties and characteristics, such as concentration, density, particle size, particle geometry, particle shape, particle porosity, and crystallographic parameters of crystal type and crystal class, of the crystalline particulate substance. Thus, measuring and determining data and information about the crystalline particle physicochemical properties and characteristics, are useful for highly accurately and reproducibly determining, understanding, classifying, and testing dissolution properties and behavior of the crystalline particulate substance. This relationship is clearly applicable to laboratory analytical testing of chemically pure crystalline particulate substances extensively performed by the biopharmaceutical, and, food and beverage industries, as described above.
There are extensive prior art methods, devices, and systems, relating to accurately and reproducibly measuring and determining physicochemical properties and characteristics of particulate substances, which are applicable to crystalline particulate substances, where these are typically based on imaging the particulate substance. Spectral imaging is currently a widely used technique for imaging particles. In spectral imaging, a particulate substance is affected in a way, for example, excitation by incident electromagnetic radiation, such as ultraviolet light upon the substance, which causes the substance to emit light featuring an emission spectra. Emitted light is recorded by an instrument such as a scanning interferometer that generates a set of interferogram images, which in turn are used to produce a spectral image, also referred to as a cube image, of the substance. Each cube (spectral) image is a three dimensional data set of voxels (volume of pixels) in which two dimensions are spatial coordinates or position, (x, y), in the substance and the third dimension is the wavelength, (xcex), of the imaged (emitted) light of the substance, such that coordinates of each voxel in a spectral image or cube image may be represented as (x, y, xcex). Any particular wavelength, (xcex), of imaged light of the substance is associated with a set of cube images or spectral fingerprints of the substance in two dimensions, for example, along the x and y directions, whereby voxels having that value of wavelength constitute the pixels of a monochromatic image of the substance at that wavelength. Each cube image, featuring a range of wavelengths of imaged light of the substance is analyzed to produce a physical location distribution or two dimensional map of the chemical composition, or, of some other physicochemical property of the substance, for example, particle size, particle geometry, or, particle shape.
An example of a method and system for real-time, on-line chemical analysis of particulate substances, for example, polycyclic aromatic hydrocarbon (PAH) particles in aerosols, in which the PAH substance is excited to emit light for example, by fluorescence, is that of U.S. Pat. No. 5,880,830, issued to Schechter, and manufactured by Green Vision Systems Ltd. of Tel Aviv, Israel, the teachings of which are incorporated by reference for all purposes as if fully set forth herein. In the disclosed method, spectral imaging techniques are implemented to acquire an image and analyze the properties of fixed position PAH particles. As part of this method, air is sampled by means of a high volume pump sucking a large volume of air featuring aerosol contaminated with PAH particles onto a substrate, followed by on-line imaging and scene analysis of the stationary particles.
A method of calibration and real-time analysis of particles is described in U.S. Pat. No. 6,091,843, to Moshe et al., the teachings of which are incorporated by reference for all purposes as if fully set forth herein. The method described, is based on using essentially the same system of U.S. Pat. No. 5,880,830, for acquiring spectral images of static particles on a filter. In brief, there is disclosed a method of analyzing particles for the presence of chemical or biological species, by spectral imaging of the particles. The output of the image acquisition is, for each imaged portion of a two-dimensional surface host to the particles, a set of images, each image at a different wavelength. These images are digitized and analyzed by standard image processing methods to produce, for each imaged portion of the two-dimensional surface, spectral images of targets, which are then compared to calibration spectral images of standard targets, for identifying and characterizing the unknown chemical or biological targets or species associated with the particles.
In the disclosure of U.S. Pat. No. 6,091,843, targets are identified in static particle images and are classified according to morphology or structural type and spectrum type. Each target is assigned a value of an extensive property. A descriptor vector is formed, where each element of the descriptor vector is the sum of the extensive property values for one target class. The descriptor vector is transformed, for example, to a vector of mass concentrations of chemical species of interest or of number concentrations of biological species of interest, using a relationship determined in the calibration procedure. In the calibration procedure, spectral images of calibration samples of static particles having known composition are acquired, and empirical morphology types and spectrum types are inferred from the spectral images. Targets are identified in the calibration spectral images, classified according to morphology type and spectrum type, and assigned values of an extensive property. For each calibration sample, a calibration descriptor vector and a calibration concentration vector is formed. A collective relationship between the calibration descriptor vectors and the calibration concentration vectors is found using chemometric methods.
In conventional scene analysis using the above described methods and systems for spectral imaging of individual particles, for example, for each scene, there is auto-focusing, where a best focal position is determined for use in analyzing or classifying particle properties. For some scenes, this is possible, and a focused image may be obtained in an automatic manner. Typically, an auto-focus module is coupled with a computer controlled mechanism that automatically changes the focal position, by moving along an axis parallel to the optical axis of the imaging or focusing sensor, thereby enabling identification of a good focal position. For other scenes, a good focal position is not guaranteed to exist and further image processing based on focus-fusion methodology is required.
When focused images of spatially varying or depth dependent scenes can not be generated by using such auto-focus electro-mechanical means, such that single focal positions can not be identified, focused representations of the scenes can be constructed by combining or fusing selected portions of several defocused images of each scene. This process is referred to as focus-fusion imaging, and the resulting images of such processing are referred to as a focus-fusion images. Defocused images, for example, those acquired during auto-focusing, are fused together such that each target in a given scene is in correct focus. Scene targets are detected by analyzing either focused images, if they exist, or, focus-fusion images.
Spectral imaging of spatially varying, depth dependent or multi-layered samples of particles is not described in the above referenced methods and systems. Imaging and image analysis of a random single two-dimensional layer of a particulate substance are ordinarily straightforward. However, multi-layer imaging and image analysis of depth dependent particulate substances, such as multi-layered dry particles, or, particles in a frozen or immobilized suspension, for example, as obtained from a pharmaceutical, or, food or beverage, particulate sample, are substantially more complex. Nevertheless, there are instances where it is necessary to obtain property and classification information of depth dependent particulate substances, in-situ, for example, as part of sampling a commercial pharmaceutical, or, food or beverage, manufacturing process. More often than not, images obtained of such particulate substances are defocused, and require special image processing techniques, such as focus-fusion, for obtaining useful information about the particulate substances.
Additionally, the above described disclosures feature useful methods and systems for acquiring and analyzing spectral images of particles, but are limited to identifying and quantifying the presence of species on particles, where the species are typically considered particle impurities, and therefore, there is no description of spectral imaging and analysis of a chemically pure particulate substance. Furthermore, there is no description of a method for applying the described pattern recognition classification procedures for analyzing and correlating xe2x80x98intra-particlexe2x80x99 spectral images of individual particles with respect to morphological or geometrical distribution and/or frequency distribution of physicochemical properties and characteristics, such as concentration, density, particle size, particle geometry, particle shape, particle porosity, and crystallographic parameters, of the at least one chemically pure particulate substance in the host particles, separate from impurity species concentration.
There is disclosed, by the same applicant of the present invention, in PCT International Patent Application No. PCT/IL01/01110, filed Dec. 2, 2001, entitled: xe2x80x9cMethod For In-situ Focus-fusion Multi-layer Spectral Imaging And Analysis Of Particulate Samplesxe2x80x9d, taking priority from recently allowed U.S. patent application Ser. No. 09/727,753, filed Dec. 4, 2000, of same title, which is a Continuation-in-Part of abandoned U.S. patent application Ser. No. 09/322,975, filed Jun. 1, 1999, of same title, which is a Continuation-in-Part of U.S. patent application Ser. No. 09/146,361 (now U.S. Pat. No. 6,091,843, previously summarized above), the teachings of which are incorporated by reference for all purposes as if fully set forth herein, a method for in-situ focus-fusion multi-layer spectral imaging and analysis of depth dependent particulate substances, which is applicable to crystalline particulate substances.
Therein, is described how three-dimensional scene analysis is performed by applying focus-fusion methodology to defocused images acquired by multi-layer spectral imaging of depth dependent particulate substances, whereby the results are shown to be quite useful for detecting and classifying in-situ physicochemical properties and characteristics, such as chemical composition, concentration, density, particle size, particle geometry, and particle shape, which ideally involve multi-layer three-dimensional image analysis.
According to the disclosure of PCT/IL01/01110, a unique method of focus-fusion is applied to focused and defocused images acquired from multi-layer spectral imaging of a depth dependent particulate substance, in order to construct a series of fused focused cube (spectral) image representations of the imaged particles, thereby generating a focused image of essentially each particle in a sample of the particulate substance. The disclosed method introduces and features the use of a uniquely defined and evaluated focus-fusion factor parameter, Fb, for correlating and integrating (1) empirically determined particle physicochemical information and parameters relating to (i) particle chemical composition and associated chemistry, and relating to (ii) particle morphology such as particle size and particle shape, with (2) empirically determined particle spectral information and parameters such as (i) pixel intensity, (ii) signal-to-noise ratio (S/N), (iii) image sharpness, (iv) spectral distances, and (v) spectral fingerprints associated with distinct spectral emission patterns of individual particles. The focus-fusion factor parameter, Fb, is used in critical steps of image detection, image analysis, and in algorithms for classification of particle properties and characteristics. This uniquely determined parameter enables achievement of high levels of accuracy and precision in detection and classification of the particulate substance, on a global scale, and of the individual particles, on a local scale.
The method disclosed in PCT/IL01/01110 includes collecting and analyzing physicochemical and multi-layer spectral data relating to the particles in the sample, including mapping of three-dimensional positions of particles, particle sizes, and of particle characteristics relating to particle emission spectra. Scene information, in the form of spectral fingerprints, used in the analysis of focus-fusion of the multi-layer spectral images is further processed in order to generate relevant in-situ physicochemical information of the particles, such as particle size distribution, particle morphological features such as structure, form, and shape characteristics, and chemical composition. The focus-fusion multi-layer spectral image analysis includes a sophisticated classification procedure for on-line (real time) extracting useful information relating to particle properties and characteristics needed for generating a statistically based and reliable report applicable to monitoring and/or controlling a wide variety of industrial processes, such as pharmaceutical, food, and beverage, manufacturing processes.
According to that disclosure, the method of focus-fusion multi-layer spectral imaging and analysis of depth dependent particulate samples can be applied to a sample of chemically pure particles, such as chemically pure crystalline particles. However, each described alternative procedure for analyzing the data of the fused cube images of the particles is with respect to either an individual particle as a whole, as the simplest unit or object of imaging and analysis, or, with respect to a sample of many such individual particles. There is no explicit, implicit, or even suggestive, description for analyzing the data, in general, of the fused cube images of the particles with respect to variation of internal or xe2x80x98intra-particlexe2x80x99 physicochemical properties and characteristics, and consequently, in that disclosure, there is no explicit, implicit, or suggestive, description for relating focus-fusion spectral image data, in particular, with respect to variation, in terms of morphological or geometrical distribution and/or frequency distribution, to internal or intra-particle physicochemical properties and characteristics such as concentration, density, particle size, particle geometry, particle shape, particle porosity, and/or crystallographic parameters, of the individual particles.
In actuality, it turns out, especially with regard to standard laboratory analytical testing of particulate substances as currently practiced by pharmaceutical, biotechnology, food, beverage, and chemical, industries, that from a more detailed, but realistic viewpoint, measuring, determining, and analyzing, physicochemical properties and characteristics of a sample of a particulate substance, such as of a chemically pure crystalline particulate substance, down to the level or scale of an individual particle as a whole, are significantly limited with respect to realistically, highly accurately and reproducibly, relating spectral imaging and/or other types of empirically obtained and/or determined physicochemical data and information to results of the laboratory analytical testing studies of particulate substances. This phenomenon is particularly evident where a chemically pure particulate substance, featuring at least one chemically pure individual compound, is heterogeneous with respect to variation, in terms of morphological or geometrical distribution and/or frequency distribution, of internal or intra-particle physicochemical properties and characteristics such as concentration, density, particle size, particle geometry, particle shape, particle porosity, and/or crystallographic parameters, of the at least one chemically pure individual compound throughout a given sized sample of the chemically pure particulate substance.
Accordingly, a need was clearly established for measuring, determining, and analyzing, empirically obtained and/or determined physicochemical data and information of particulate substances, with respect to variation, in terms of morphological or geometrical distribution and/or frequency distribution, of internal or intra-particle physicochemical properties and characteristics of the particulate substances, for improving analysis and understanding of the physicochemical properties, characteristics, and behavior, of the particulate substances, thereby, improving current applications and developing new applications of particulate substances for those industries, such as the biopharmaceutical, food, and beverage, industries, which process particulate substances in the form of raw materials and/or finished products.
The same applicant as the present invention, in PCT International Patent Application No. IL01/00366, filed Apr. 19, 2001, entitled xe2x80x9cMethod For Generating Intra-particle Morphological Concentration/Density Maps And Histograms Of A Chemically Pure Particulate Substancexe2x80x9d, taking priority from U.S. Provisional Patent Application No. 60/198,556, filed Apr. 20, 2000, the teachings of which are incorporated by reference for all purposes as if fully set forth herein, disclose a method for spectral imaging, in general, and focus-fusion multi-layer spectral imaging, in particular, combined with appropriate pattern recognition classification analysis, performed on a number of individual particles of a plurality of particles of a chemically pure particulate substance, for forming a plurality of sets of single-particle spectral fingerprint data, where each set is characterized by a single-particle spectral fingerprint spectrum.
According to the method disclosed in PCT/IL01/00366, in each set of single-particle spectral fingerprint data, shifts in spectral parameters, also referred to as xe2x80x98spectral shiftsxe2x80x99, are identified, for forming an intra-particle region group featuring a plurality of sub-sets of intra-particle spectral fingerprint pattern data. Each sub-set is characterized by an intra-particle spectral fingerprint pattern spectrum, which is associated with the same single-particle spectral fingerprint spectrum as the other intra-particle spectral fingerprint pattern spectra of the other sub-sets in the same intra-particle region group. Each intra-particle region group is associated with a plurality of intra-particle morphological region type identifiers, where each intra-particle morphological region type identifier is associated with a surface concentration value and a density value of the chemically pure substance in that imaged particle, for forming a set of intra-particle morphological concentration/density data. For each particle, the set of intra-particle morphological concentration/density data is used for generating an intra-particle morphological concentration/density map for illustrating local, intra-particle, morphological distribution of surface concentration and density of the chemically pure substance throughout the imaged particle. For that number of imaged and analyzed particles of the plurality of particles of the particulate substance, a morphological concentration/density histogram, or frequency distribution, is generated from a plurality of sets of the intra-particle morphological concentration/density data, for illustrating a statistically based global morphological distribution of concentration and density throughout the entire chemically pure particulate substance.
The method disclosed in PCT/IL01/00366, introducing and featuring the newly determined sub-classification of spectral imaging data, in general, and of focus-fusion multi-layer spectral imaging data, in particular, illustrates how it is possible, by way of identifying, analyzing, and correlating spectral shifts, to associate different spectral fingerprint patterns of the same particle with different intra-particle morphological regions varying in concentration and/or density of the chemically pure, but morphologically heterogeneous, particulate substance. The novelty of that method is based on identifying shifts in spectral parameters, for example, emission wavelength and/or emission intensity or amplitude, present in classified spectral imaging spectral fingerprint data, in general, and based on identifying shifts in spectral parameters in classified focus-fusion multi-layer spectral imaging spectral fingerprint data, in particular, and using the identified spectral shift data for revealing, correlating, and displaying intra-particle morphological and concentration/density data in the forms of intra-particle morphological concentration/density maps and histograms of the chemically pure particulate substance, which are representative of, and directly applicable to, intra-particle physicochemical analysis and characterization of a chemically pure particulate substance.
The method of that invention, compared to currently used methods, provides new capabilities for effectively and efficiently determining and classifying intra-particle morphological concentration/density data and related information, for application to a wide variety of industries requiring intra-particle physicochemical analysis and characterization of chemically pure particulate substances, such as chemically pure crystalline particulate substances. That invention is especially well suited for analyzing spectral images of chemically pure particulate substances of medicines, for example, medicines containing both chemically pure active ingredients and chemically pure inactive ingredients, whereby there is distinguishing and characterizing physicochemical properties, characteristics, and behavior, of both active and inactive ingredients.
As previously stated above, in the field of commercial handling, processing, and manufacturing, of crystalline particulate substances, including analysis and control thereof, especially as applied in the biopharmaceutical industry, there is on-going interest, resources, and activities, being devoted to techniques for measuring, determining, and analyzing, physicochemical data and information relating to crystallographic properties, characteristics, and parameters, of crystalline particulate substances, in general, and of chemically pure crystalline particulate substances, in particular. The above is especially relevant when involving chemically pure crystalline particulate substances each featuring or characterized by more than one unique set of crystallographic parameters of crystal type and crystal class.
More specifically, for example, in a chemically pure crystalline particulate substance, one or more of the at least one chemically pure individual chemical compound may exhibit isomerism, involving the existence of a variety of structural isomers and/or stereoisomers of the same chemically pure crystalline particulate substance, typically, characterized by a corresponding variety of different crystallographic parameters of crystal type and crystal class. To a lesser, but, nevertheless, still noticeable, extent or degree of structural or crystallographic difference, one or more of the at least one chemically pure individual chemical compound may exhibit polymorphism, involving crystallization of a compound in at least two distinct forms, giving rise to the existence of a variety of structurally different polymorphs of the same chemically pure crystalline particulate substance, typically, characterized by a corresponding variety of different crystallographic parameters of crystal type and crystal class.
Moreover, in such cases, according to extent of separation and purification processes included in the overall manufacturing processes involving the chemically pure crystalline particulate substance, the chemically pure crystalline particulate substance is expected to be heterogeneous to some degree or extent with respect to morphological or geometrical distribution and/or with respect to frequency distribution of crystallographic parameters of crystal type and crystal class, of the at least one chemically pure individual compound throughout a given sized sample of the chemically pure crystalline particulate substance.
It is well known and very relevant to the biopharmaceutical industry, that different isomers and/or polymorphs of the same chemically pure crystalline particulate substance may exhibit significantly different physicochemical properties and characteristics, such as those related to crystallographic parameters, giving rise to significantly different behavior, efficacy, and therapeutic effects, when subjected to the same laboratory in-vitro conditions and/or clinical in-vivo conditions.
An excellent, realistic example of current concern, of this phenomenon relates to a patented brand name drug, and an almost identical generic substitute drug, each marketed to and consumed by post-menopausal women exhibiting symptoms of osteoporosis. Both drugs contain the identically same active ingredient, alendronic acid. However, while the patented brand name drug is manufactured, sold, and consumed, as a sodium trihydrate, having xe2x80x98threexe2x80x99 water molecules in the crystalline particulate structure, the almost identical generic substitute drug is manufactured, sold, and consumed, as a sodium monohydrate, having a xe2x80x98singlexe2x80x99 water molecule in the crystalline particulate structure. In time, a clinically statistically significant number of women consuming the sodium monohydrate generic substitute drug developed and exhibited a wide variety of undesirable and/or severe physiological symptoms and medical conditions, apparently directly related to their consumption of the sodium monohydrate generic substitute drug, which were not reported by similar women consuming the sodium trihydrate brand name drug.
From the example just described, it is clearly expected, and may be concluded a priori, that intra-particle crystallographic parameters of crystal type and crystal class of particles of the sodium monohydrate drug are measurably different from those of particles of the sodium monohydrate drug, to the extent that the previously described phenomenon takes place. In this case, crystallographic parameters can therefore be used as criteria of quality control and/or quality assurance testing during the manufacturing of the drug. This represents just one example of the need for the present invention, of a method for generating intra-particle crystallographic parameter maps and histograms of a chemically pure crystalline particulate substance, by spectral imaging of individual particles of the chemically pure crystalline particulate substance and analyzing the spectral images using pattern recognition classification analysis, which is not fulfilled by implementing prior art techniques and methodologies of spectral imaging of particles.
In the disclosure of PCT/IL01/00366 it is stated xe2x80x9cthat spectral shifts present in a given group of intra-particle spectral fingerprint patterns of an individual particle are primarily due to local, intra-particle, variation or heterogeneity in particle morphology such as shape or geometry, and porosity, and due to local, intra-particle, variation or heterogeneity in surface concentration and/or density of the chemically pure substancexe2x80x9d. An important aspect of particle morphology regarding particle shape or geometry, not mentioned or described in, and not obviously derived from, the prior art of spectral imaging, in general, or from the disclosure of PCT/IL01/00366, in particular, is that of crystallographic parameter characterization of crystalline particles, and of crystalline particulate substances consisting of and/or including crystalline particles in their compositions. To date, the inventor of the present invention is unaware of a prior art teaching of a method for generating intra-particle crystallographic parameter maps and histograms of a chemically pure crystalline particulate substance by spectral imaging of individual particles of the chemically pure crystalline particulate substance and analyzing the spectral images using pattern recognition classification analysis.
There is thus a need for, and it would be highly advantageous to have a method for generating intra-particle crystallographic parameter maps and histograms of a chemically pure crystalline particulate substance by spectral imaging, in general, and by focus-fusion multi-layer spectral imaging, in particular, of individual particles of the chemically pure crystalline particulate substance and analyzing the spectral images using pattern recognition classification analysis. Moreover, there is a need for such a method which is applicable to a variety of industries, such as the biopharmaceutical, food, and beverage, industries, currently devoting significant amounts of resources towards better measurement analysis, understanding, and application, of crystallographic data, information, and parameters, of chemically pure crystalline particulate substances in the form of raw materials and/or finished products. Additionally, there is a particular need especially relevant to those sectors of the biopharmaceutical industry currently or considering developing, testing, and manufacturing, pharmaceutical products which include chemically pure crystalline particulate substances featuring different isomers and/or polymorphs exhibiting significantly different physicochemical properties and characteristics that are a function of crystallographic parameters, giving rise to significantly different behavior, efficacy, and therapeutic effects, when subjected to the same laboratory in-vitro conditions and/or clinical in-vivo conditions.
The present invention relates to a method for generating intra-particle crystallographic parameter maps and histograms of a chemically pure crystalline particulate substance by spectral imaging, in general, and by focus-fusion multi-layer spectral imaging, in particular, of individual particles of the chemically pure crystalline particulate substance and analyzing the spectral images using pattern recognition classification analysis.
Thus, according to the present invention, there is provided a method for generating intra-particle crystallographic parameter maps and histograms of a chemically pure crystalline particulate substance, comprising the steps of. (a) acquiring a set of spectral images by a spectral imaging system for each of a number of particles of the chemically pure crystalline particulate substance having a plurality of the particles; (b) performing pattern recognition classification analysis on each set of the acquired spectral images for each imaged particle, for forming a number of sets of single-particle spectral fingerprint data; (c) identifying at least one spectral shift in each set of single-particle spectral fingerprint data associated with each imaged particle, for forming an intra-particle crystallographic region group featuring a plurality of sub-sets of intra-particle spectral fingerprint pattern data, where selected data elements in each sub-set are shifted relative to corresponding data elements in each remaining sub-set in the same intra-particle crystallographic region group; (d) forming a set of intra-particle crystallographic parameter data relating to each imaged particle from each intra-particle crystallographic region group; (e) generating each of the intra-particle crystallographic parameter maps from each set of the intra-particle crystallographic parameter data; and (f) generating each of the crystallographic parameter histograms from a plurality of the sets of the intra-particle crystallographic parameter data, for illustrating a statistically based global morphological or geometrical frequency distribution of crystallographic parameters of the chemically pure particulate crystalline substance throughout the chemically pure crystalline particulate substance.
According to further features in preferred embodiments of the invention described below, the chemically pure crystalline particulate substance is a crystalline particulate substance including a plurality of crystalline particles each having at least one chemically pure individual chemical compound.
According to further features in preferred embodiments of the invention described below, the at least one chemically pure individual chemical compound exhibits isomerism and/or polymorphism, and has a number of isomers and/or a number of polymorphs.
According to further features in preferred embodiments of the invention described below, the chemically pure crystalline particulate substance is heterogeneous with respect to morphological or geometrical distribution of crystallographic parameters of crystal type and crystal class, of at least one chemically pure individual compound throughout a sample of the chemically pure crystalline particulate substance.
According to further features in preferred embodiments of the invention described below, the physicochemical properties and characteristics of the chemically pure crystalline particulate substance are selected from the group consisting of independent of particle depth and dependent of particle depth.
According to further features in preferred embodiments of the invention described below, the chemically pure crystalline particulate substance is selected from the group consisting of a separate stand alone powdered entity or substance, and a powdered entity or substance part of another entity or substance in a solid or liquid phase having a function selected from the group consisting of as a substrate of, containing, hosting, delivering, receiving, and combinations thereof, the chemically pure crystalline particulate substance.
According to further features in preferred embodiments of the invention described below, the chemically pure crystalline particulate substance is a powder in a form selected from the group consisting of a powder and a powder mixture. The powder is in a configuration or form selected from the group consisting of loose or free flowing, packed, compacted, and combinations thereof The powder is composed of components selected from the group consisting of inorganic components, organic components, and combinations thereof The powder is of origin or derivation selected from the group consisting of natural origin or derivation, synthetic origin or derivation, and combinations thereof
According to further features in preferred embodiments of the invention described below, the chemically pure crystalline particulate substance is a raw material used in manufacturing a product selected from the group consisting of a pharmaceutical product, a food product, and a beverage product.
According to further features in preferred embodiments of the invention described below, the chemically pure crystalline particulate substance is selected from the group consisting of a medicinal or therapeutic powder, a high performance powdered chemical, and a powdered biological specimen. The medicinal or therapeutic powder is part of a pharmaceutical product in a form selected from the group consisting of a tablet a capsule, a caplet, a loose powder, a gel, a liquid suspension, and a liquid solution.
According to further features in preferred embodiments of the invention described below, in step (a), the spectral images are focus-fusion multi-layer spectral images acquired by focus-fusion multi-layer spectral imaging of the particles of the chemically pure crystalline particulate substance.
According to another aspect of the present invention, there is provided a method for identifying and illustrating intra-particle morphological or geometrical distribution of crystallographic parameters of a chemically pure crystalline particulate substance, comprising the steps of: (a) acquiring a set of spectral images by a spectral imaging system for each of a number of particles of the chemically pure crystalline particulate substance having a plurality of the particles; (b) performing pattern recognition classification analysis on each set of the acquired spectral images for each imaged particle, for forming a number of sets of single-particle spectral fingerprint data; (c) identifying at least one spectral shift in each set of single-particle spectral fingerprint data associated with each imaged particle, for forming an intra-particle crystallographic region group featuring a plurality of sub-sets of intra-particle spectral fingerprint pattern data, where selected data elements in each sub-set are shifted relative to corresponding data elements in each remaining sub-set in same intra-particle crystallographic region group; (d) forming a set of intra-particle crystallographic parameter data relating to each imaged particle from each intra-particle crystallographic region group; and (e) generating a plurality of intra-particle crystallographic parameter maps and histograms from a plurality of the sets of the intra-particle crystallographic parameter data, for identifying and illustrating the intra-particle morphological or geometrical distribution of the crystallographic parameters of the chemically pure particulate crystalline substance throughout the chemically pure crystalline particulate substance.
The present invention successfully provides a new, highly accurate and reproducible, method for generating and applying intra-particle crystallographic parameter data and information of a chemically pure crystalline particulate substance by spectral imaging, in general, and by focus-fusion multi-layer spectral imaging, in particular, combined with analyzing the spectral images using pattern recognition classification analysis, and widens the scope of presently known techniques and methods for spectral imaging of particulate substances. Additionally, the method of the present invention is applicable to a variety of industries, such as the biopharmaceutical, food, and beverage, industries, currently devoting significant amounts of resources towards better measurement analysis, understanding, and application, of crystallographic data, information, and parameters, of chemically pure crystalline particulate substances in the form of raw materials and/or finished products.
Implementation of the method of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and/or equipment used for implementing a particular preferred embodiment of the disclosed method, several selected steps of the present invention could be performed by hardware, by software on any operating system of any firmware, or a combination thereof. In particular, as hardware, selected steps of the invention could be performed by a computerized network, a computer, a computer chip, an electronic circuit, hard-wired circuitry, or a combination thereof, involving any number of digital and/or analog, electrical and/or electronic, components, operations, and protocols. Additionally, or alternatively, as software, selected steps of the invention could be performed by a data processor, such as a computing platform, executing a plurality of computer program types of software instructions or protocols using any suitable computer operating system.